Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that affects women during the childbearing years. Among other clinical manifestations, pregnancy loss is a common occurrence. Studies have shown that women diagnosed with SLE prior to completing their families have fewer children than desired, largely due to pregnancy loss. Past research into SLE related pregnancy morbidity has focused largely on late pregnancy complications rather than early pregnancy loss (spontaneous abortion, Sab). Aside from genetic and structural abnormalities, the antiphospholipid antibody syndrome is the most well studied predictor of pregnancy loss; however, it accounts for a small fraction of recurrent pregnancy loss (RPL). Evidence suggests a possible immunologic role for some cases of RPL, including both auto- and alloimmune disturbances. Fetal micro-chimerism, the bi-directional transfer of maternal and fetal cells, DNA, and proteins during normal pregnancy, is increased in complicated pregnancies (placental abruption, prematurity, and pre-eclampsia), fetal loss [23], and termination, presumably due to increased maternal-fetal transfusion. Previous pregnancies, therefore, afford the maternal immune system access to novel fetal antigens: allo-sensitization that may trigger abnormal immune responses, leading to cytotoxic damage to subsequent embryos if maternal peripheral tolerance is not achieved. Dr. Miklos, part of the leadership team of this application, has developed specific ELISA and corresponding autoantigen microarrays against minor histocompatibility antigens encoded by the Y- chromosome, H-Y antigens. Presence of high titer H-Y antibodies, but not their H-X homologues, has been seen in 46% of patients with RPL and is associated with a decreased male:female ratio in subsequent live births. We have recently demonstrated a lower than expected male:female ratio in lupus families in the Lupus Family Registry and Repository (LFRR); however, neither H-Y nor H-X antibodies have been systematically studied in this or other SLE cohorts. We hypothesize that the prevalence of multiple high-titer novel and traditional autoantibodies occurs more frequently in SLE patients compared to healthy, unrelated women. Further, such antibodies are associated with Sab and RPL independent of APL. In particular, decreased male birth rates among SLE patients implicate anti-male immunity in SLE women, and H-Y antibodies will be detected in SLE women with frequent Sab and RPL. We propose to study the prevalence of these antibodies and their associations with SAB and RPL among SLE patients, their sisters, and unrelated healthy women in order to develop a predictive model for patients at highest risk for pregnancy loss.